Mechanistic dissection of dominant AIRE mutations in mouse models reveals AIRE autoregulation

Goldfarb, Yael; Givony, Tal; Kadouri, Noam; Dobeš, Jan; Peligero-Cruz, Cristina; Zalayat, Itay; Damari, Golda; Dassa, Bareket; Ben‐Dor, Shifra; Gruper, Yael; Oftedal, Bergithe E.; Bratland, Eirik; Erichsen, Martina M.; Berger, A; Avin, Ayelet; Nevo, Shir; Haljasorg, Uku; Kuperman, Yael; Ulman, Adi; Haffner-Krausz, Rebecca; Porat, Ziv; Atasoy, Ulus; Leshkowitz, Dena; Husebye, Eystein S.; Abramson, Jakub

doi:10.1084/jem.20201076

Cited by 18 publications

(36 citation statements)

References 84 publications

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“…Moreover, several dominant-negative AIRE mutations have now been recognized within the SAND and PHD1 domains of the gene and exhibit varying degrees of dominant negative effects in vitro and in mice ( 20 – 25 ). Affected patients typically develop milder APECED with fewer autoimmune manifestations compared to patients with classical APECED, while some patients remain unaffected without autoimmunity, indicative of incomplete clinical penetrance ( 21 ).…”

Section: Genetics Of Apecedmentioning

confidence: 99%

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

2021

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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type-1 (APS-1), is a rare monogenic autoimmune disease caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene. AIRE deficiency impairs immune tolerance in the thymus and results in the peripheral escape of self-reactive T lymphocytes and the generation of several cytokine- and tissue antigen-targeted autoantibodies. APECED features a classic triad of characteristic clinical manifestations consisting of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenal insufficiency (Addison's disease). In addition, APECED patients develop several non-endocrine autoimmune manifestations with variable frequencies, whose recognition by pediatricians should facilitate an earlier diagnosis and allow for the prompt implementation of targeted screening, preventive, and therapeutic strategies. This review summarizes our current understanding of the genetic, immunological, clinical, diagnostic, and treatment features of APECED.

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Section: Genetics Of Apecedmentioning

confidence: 99%

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

2021

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“…Putative FOXN1 TFBSs also exist in the HFC-specific AR5 and AR7, suggesting that FOXN1 might participate in an autoregulatory loop in HFCs as well. The role of FOXN1 in autoregulation is not surprising because many other TFs are known to regulate their own expression via either positive or negative feedback loops, including HNF1A, HNF4A, HNF6, FOXA2, CREB1 ( 61 ), BRN3A ( 62 ), AIRE ( 63 ), and MYOD1 ( 64 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional regulation of the thymus master regulator Foxn1

et al. 2022

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FOXN1 is a transcription factor critical for the development of both thymic epithelial cell (TEC) and hair follicle cell (HFC) compartments. However, mechanisms controlling its expression remain poorly understood. To address this question, we performed thorough analyses of the evolutionary conservation and chromatin status of the Foxn1 locus in different tissues and states and identified several putative cis-regulatory regions unique to TECs versus HFCs. Furthermore, experiments using genetically modified mice with specific deletions in the Foxn1 locus and additional bioinformatic analyses helped us identify key regions and transcription factors involved in either positive or negative regulation of Foxn1 in both TECs and HFCs. Specifically, we identified SIX1 and FOXN1 itself as key factors inducing Foxn1 expression in embryonic and neonatal TECs. Together, our data provide important mechanistic insights into the transcriptional regulation of the Foxn1 gene in TEC versus HFC and highlight the role of FOXN1 in its autoregulation.

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“…Some of the dominant-negative mutations causing APS-1 in humans have also been introduced in mice. Using mice on the NOD background, the mice showed spontaneous immune infiltrations in the liver, prostate, and salivary glands, with a partially inhibited TRA repertoire and developed neuropathy and early-onset diabetes [96,97], indicating the importance of quantitative changes in thymic antigen expression in the development of organ-specific autoimmunity.…”

Section: B Cells In Aire-deficient Mice Varies With Genetic Strain and Aire Mutationsmentioning

confidence: 99%

B Cells and Autoantibodies in AIRE Deficiency

et al. 2021

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Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare but severe monogenetic autoimmune endocrine disease caused by failure of the Autoimmune Regulator (AIRE). AIRE regulates the negative selection of T cells in the thymus, and the main pathogenic mechanisms are believed to be T cell-mediated, but little is known about the role of B cells. Here, we give an overview of the role of B cells in thymic and peripheral tolerance in APS-1 patients and different AIRE-deficient mouse models. We also look closely into which autoantibodies have been described for this disorder, and their implications. Based on what is known about B cell therapy in other autoimmune disorders, we outline the potential of B cell therapies in APS-1 and highlight the unresolved research questions to be answered.

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Mechanistic dissection of dominant AIRE mutations in mouse models reveals AIRE autoregulation

Cited by 18 publications

References 84 publications

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Transcriptional regulation of the thymus master regulator Foxn1

B Cells and Autoantibodies in AIRE Deficiency

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